MINI-REVIEW

Favipiravir: Pharmacokinetics and Concerns

About Clinical Trials for 2019-nCoV Infection
Yin-Xiao Du1,2,3 and Xiao-Ping Chen1,2,3,*

An outbreak of 2019-nCoV infection has spread across the world. No specific antiviral drugs have been approved
for the treatment of COVID-2019. In addition to the recommended antiviral drugs, such as interferon-ɑ, lopinavir/
ritonavir, ribavirin, and chloroquine phosphate, some clinical trials focusing on virus RNA-dependent RNA polymerase
(RdRp) inhibitors have been registered and initiated. Favipiravir, a purine nucleic acid analog and potent RdRp
inhibitor approved for use in influenza, is also considered in several clinical trials. Herein, we summarized the
pharmacokinetic characteristics of favipiravir and possible drug–drug interactions from the view of drug metabolism.
We hope this will be helpful for the design of clinical trials for favipiravir in COVID-2019, as data regarding in vitro
virus inhibition and efficacy in preclinical animal studies are still not available.

An outbreak of 2019-novel coronavirus (nCoV) infection, a
diseased called the new coronavirus pneumonia (NCP) by the
Chinese government and later named as COVID-19 by the
World Health Organization (WHO) on February 11, 2020, has
spread across the world since the first case in December 2019 from
Wuhan, China. As of April 1, 2020, 874,151 cases have been di-
agnosed worldwide, and 43,804 have died from the pandemic.
However, no specific antiviral drugs have been approved for the
treatment of COVID-19. Interferon-ɑ, lopinavir/ritonavir, riba-
virin, chloroquine phosphate, arbidol, and combinations of these
drugs are recommended by the seventh update of the Chinese
National Health Commission’s Treatment Regimen. In the mean-
time, other possible urgent prevention and treatment options are
discussed elsewhere.1,2 Currently, there are >  100 clinical trials
designed to test pre-existing US Food and Drug Administration
(FDA) approved drugs and experimental antiviral agents, which
have been proved to be safe and effective in other viral infections.
Additionally, traditional Chinese medicines have been regis-
tered at the time of the submission of this manuscript. Favipiravir
is one of the antiviral candidates involved in the clinical trials.3
To provide useful information for the dosing regimen and study
design with favipiravir, a mini-review focused on the pharmaco-
kinetic characteristics of favipiravir and the potential drug–drug
interactions (DDIs) is presented here.
ANTIVIRAL TREATMENT FOR COVID-19 AND POTENTIAL
USE OF FAVIPIRAVIR
Favipiravir (T705), a purine nucleic acid analog, is one of the an-
tiviral candidates considered in several clinical trials (Table 1) to
evaluate the safety and efficacy in patients with NCP. Emergency
approval of favipiravir (formulation: tablet, 0.2 g) for a clinical trial
in adult patients with NCP (2020L00005) was also announced by
the National Medical Products Administration (NMDA) in China.
Favipiravir is a pyrazine carboxamide derivative (6-fluoro-3-hy-
droxy-2-pyrazinecarboxamide) and a broad-spectrum antiviral
drug approved in Japan for the treatment of influenza.4 Favipiravir
is a prodrug that is ribosylated and phosphorylated intracellularly
to form the active metabolite favipiravir ibofuranosyl-5′-triphos-
phate (T-705-RTP).4 T-705-RTP competes with purine nucleo-
sides and interferes with viral replication by incorporation into the
virus RNA and thus, potentially inhibiting the RNA dependent
RNA polymerase (RdRp) of RNA viruses (Figure 1).5 T-705-RTP
inhibits RdRp of the influenza virus with an half-maximal inhibi-
tory concentration (IC50) of 0.022 µg/mL, but does not affect the
human DNA polymerases α, β, and γ subunits at up to 100 µg/mL.5
In addition to the inhibition of influenza virus, favipiravir shows
inhibitory effects on a wide range of RNA viruses, such as arena-
virus, bunyavirus, flavivirus, and filoviruses causing hemorrhagic
fever.4 During the 2014–2015 Ebola virus (EBOV) outbreak ini-
tiated in West Africa, a proof-of-concept trial with favipiravir was
carried out in Guinea, and patients treated with favipiravir showed
a trend toward improved survival.6 In patients with an initial di-
agnosis of Ct ≥  20 for the EBOV RNA, on-trial mortality was
20.0% (95% confidence interval 11.6–32.4), which was 33% lower
than the target value (30%). A retrospective analysis of patients
with Ebola virus disease (EVD) indicated that, in comparison with
patients who received the WHO-recommended supportive ther-
apy, those who accepted additional favipiravir treatment showed
a higher overall survival rate and longer average survival time, and
a higher percentage of patients with a > 100-fold viral load reduc-
tion.7 Genome sequencing of the 2019-nCoV identified the virus
as a single-stranded RNA beta-coronavirus with the RdRp gene

1
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China; 2Institute of Clinical Pharmacology, Hunan
Key Laboratory of Pharmacogenetics, Central South University, Changsha, Hunan, China; 3National Clinical Research Center for Geriatric
Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China. *Correspondence: Xiao-Ping Chen (chenxiaoping@csu.edu.cn)
[Correction added on 30 April 2020, after first online publication: The first sentence in Abstract has been changed to ‘An outbreak of 2019-nCoV infection has
spread across the world’].
Linked article: This article is linked to Letter to the Editor by Eloy, P. et al., Clin. Pharmacol. Ther. 108, 188 (2020) https://doi.org/10.1002/cpt.1877
and Response Letter to Editor by Du, Y.-X. and Chen, X.-P. Clin. Pharmacol. Ther. 108, 190 (2020) https://doi.org/10.1002/cpt.1878.
Received March 2, 2020; accepted April 2, 2020. doi:10.1002/cpt.1844

242 CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 108 NUMBER 2 | August 2020
 Table 1  Registered clinical trials with favipiravir for the treatment of COVID-19
Registration number Design
ChiCTR2000029544 Randomized controlled
trial
ChiCTR2000029548 Randomized, open-label,
controlled trial
ChiCTR2000029600 Nonrandomized
controlled trial
ChiCTR2000029996 Randomized controlled
trial
CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 108 NUMBER 2 | Month 2020
ChiCTR2000030113 Randomized controlled
trial
ChiCTR2000030254 Randomized controlled
trial
ChiCTR2000030894 Randomized controlled
trial
ChiCTR2000030987 Randomized controlled
trial
CT, computed tomography; NEWS, national early warning score; PCR, polymerase chain reaction; RT-PCR, real-time polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
243
Intervention Outcomes
Group A (n = 10): Current antiviral treatment plus BaloxavirMarboxil tablets. 1. Time to viral negativity by RT-PCR.
Group B (n = 10): Current antiviral treatment plus favipiravir tablets. 2. Time to clinical improvement.
Group C (n = 10): Current antiviral treatment.
Group A (n = 10): BaloxavirMarboxil: 80 mg on day 1, 80 mg on day 4; 80 mg 1. Time to viral negativity by RT-PCR.
on day 7 as necessary. No more than 3 times administration in total. 2. Time to clinical improvement: Time from
Group B (n = 10): Favipiravir: 600 mg t.i.d. with 1,600 mg first loading dosage, start of study drug to hospital discharge or
no more than 14 days. to NEWS < 2 for 24 hours.
Group C (n = 10): Lopinavir-Ritonavir: 200 mg/50 mg, twice daily, for 14 days.
Group A (n = 30): Alpha-interferon atomization. 1. Declining speed of SARS-CoV-2 by PCR.
Group B (n = 30): Lopinavir and Ritonavir plus alpha-interferon atomization. 2. Negative time of SARS-CoV-2 by PCR.
Group C (n = 30): Favipiravir plus alpha-interferon atomization. 3. Incidence rate of chest imaging.
4. Incidence rate of liver enzymes.
5. Incidence rate of kidney damage.
Group A (n = 20): Favipiravir tablets; 200 mg; oral; twice a day. The adult dose 1. Time to clinical recovery.
is 1,600 mg per time on first day; the duration of treatment will be 10 days.
Group B (n = 20): Favipiravir tablets; 200 mg; oral; twice a day. The adult
dose is 1,800 mg per time on the first day; the duration of treatment will be
10 days.
Group C (n = 20): Favipiravir tablets; 200 mg; oral; twice a day. The adult dose
is 2,400 mg per time on first day; the duration of treatment will be 10 days.
Group A (n = 15): Keep ritonavir/ritonavir treatment. 1. Blood routine tests.
Group B (n = 15): Favipiravir. 2. Liver function examination.
3. Renal function examination.
4. Blood gas analysis.
5. Chest CT examination.
Group A (n = 120): Favipiravir tablets. 1. Clinical recovery rate of day 7.
Group B (n = 120): Arbidol tablets.
Group A (n = 90): Favipiravir combined with Tocilizumab. 1. Clinical cure rate.
Group B (n = 30): Favipiravir.
Group C (n = 30): Tocilizumab.
Group A (n = 50): The oral trial drug favipiravir tablets plus chloroquine 1. Improvement or recovery of respiratory
phosphate tablets. symptoms.
Group B (n = 50): Oral trial drug favipiravir tablets. 2. Viral nucleic acid shedding.
Group C (n = 50): Oral placebo treatment.
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Figure 1  Mechanism of action of favipiravir (T-705) against the virus. Favipiravir is incorporated into cells and converted to favipiravir
ibofuranosyl-5′-triphosphate (favipiravir-RTP) by host cells. The triphosphate form, favipiravir-RTP, inhibits the activity of RNA dependent RNA
polymerase (RdRp) of RNA viruses. AO, aldehyde oxidase; RMP, ribosyl monophosphate.
similar to those of severe acute respiratory syndrome coronavirus
2 (SARS-CoV-2) SARS-CoV-2 and Middle East respiratory syn-
drome coronavirus 2 (MERS-CoV-2).8–10 Therefore, favipiravir
is considered as one of the potential candidates for COVID-19,2
although confirmed in vitro and preclinical animal studies are not
available yet. A clinical trial to evaluate the safety and efficacy of fa-
vipiravir in the treatment of COVID-19 (ChiCTR2000029600)
was conducted in Shenzhen, with 80 patients recruited.11 The
results showed that the 35 patients in the favipiravir arm demon-
strated significantly shorter viral clearance time as compared with
the 45 patients in the control arm (median 4  days vs. 11  days).
X-ray examinations confirmed a higher rate of improvement in
chest imaging in the favipiravir arm (91.43% vs. 62%).11 A mul-
ticentered randomized clinical study (ChiCTR200030254) also
suggested effective control of favipiravir on COVID-19.12 For
ordinary patients with COVID-19, 7  day’s clinical recovery rate
increased from 55.86% to 71.43% with favipiravir treatment. For
ordinary patients with COVID-19 and patients with hypertension
and/or diabetes, the time of fever reduction and cough relief in the
favipiravir treatment group was also decreased significantly.12
PHARMACOKINETICS OF FAVIPIRAVIR
Studies from healthy Japanese volunteers showed that the maxi-
mum plasma concentration of favipiravir occurred at 2 hours after
oral administration, and then decreased rapidly with a short half-
life time of 2–5.5 hours.13 The plasma protein binding of favipira-
vir was 54% in humans.14 The bound percentages of favipiravir to
human serum albumin and α1-acid glycoprotein were 65.0% and
244
6.5%, respectively.15 The parent drug undergoes metabolism in the
liver mainly by aldehyde oxidase (AO), and partially by xanthine
oxidase, producing an inactive oxidative metabolite T-705M1 ex-
creted by the kidneys.13 The rapid appearance of favipiravir in the
liver, followed by the gall bladder and segments of the intestinal tract
after venous injection in mice, suggests rapid excretion of favipira-
vir by the liver in mice.16 Pharmacokinetic analysis of intravenous
favipiravir in cynomolgus macaques after repeated doses indicates
obvious nonlinear pharmacokinetics over time and over a range
of doses, and a continuous decline in plasma concentration after
7 days of continuous administration in the nonhuman primates is
also observed.17 Data obtained from 66 patients for experimental
treatment with favipiravir for EVD (named as the JIKI trial) indi-
cated that the steady-state trough concentration notably decreased
on day 4 (25.9 µg/mL) as compared with day 2 (46.1 µg/mL), which
supports a decrease in drug concentration after continuous use.18
To further understand the in vivo biodistribution and kinetics
of uptake and clearance of favipiravir after a single and repeated
administration, an 18F radiolabeled favipiravir ([18F]favipiravir)
was developed.16 Dynamic distribution of [18F]favipiravir was
assessed by positron emission tomography dynamic scans and
gamma counting in naïve mice and favipiravir predosed mice
(oral administration, loading dose: 250 mg/kg b.i.d., day 1; main-
taining dose: 150 mg/kg, twice daily for 3 days) as well. In naïve
mice, tail venous injection of [18F]favipiravir resulted in rapid
uptake and clearance through the liver, kidneys, and intestine.
In contrast, in the predosed mice, the plasma concentration de-
creased by 25–50% and tissue distributions in the liver, stomach,
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brain, and muscle tissue increased 2–5 times.16 On the assump-
tion that tissue retention of favipiravir is dependent on its ribo-
sylated and phosphorylated form, the increased distribution by
predosing or chronic use is supposed to promote cellular uptake
and the antiviral efficacy of the drug. In vitro study indicates that
favipiravir can inhibit AO activity in concentration-dependent
and time-dependent manners, which explains self-inhibition of
the inactivation metabolism of the parent drug and increased
plasma parent/inactive metabolite ratio (T705/T705M1) after
chronic dosing.13 An increase in circulating T-705/T-705M1
ratio in mice is supposed to facilitate the cellular uptake and
trapping of favipiravir in the tissue by increasing the extracellular
to an intracellular concentration gradient.16 This helps explain
the accelerated circulating clearance of favipiravir after repeated
administration. However, solid evidence from monitoring the
tissue levels of T-705-RTP during continuous favipiravir use
is warranted. T-705-RTP is also formed in human peripheral
blood mononuclear cells (PBMCs),13 and terminal half-life (t1/2)
of T-705-RTP was about 2  hours in PBMCs. Although t1/2 of
T-705-RTP in PBMCs was shorter than that in the lung (t1/2 of
about 4.2  hours),15 we suggest that detection of T-705-RTP in
PBMCs may serve as a surrogate considering the availability of
peripheral blood.
THE DOSING REGIMEN OF FAVIPIRAVIR IN COVID-19
Dosing regimen is critical in clinical trials for antiviral purposes.
The IC50 of favipiravir varies from nanomolar to micromolar
concentrations depending on viral studies.4 Therefore, dosage
requirements and regimens may be different among treatments.
The approved favipiravir regimen for influenza in Japan includes
a 3,200 mg oral loading dose (1,600 mg every 12 hours) on day 1,
followed by 600  mg twice daily on days 2–5.19 Higher regimen
(1,800 mg twice daily on day 1 followed by 800 mg twice daily
thereafter) is also adopted in phase III.19 Safety and efficacy of
this regimen in influenza has been confirmed.13 The main adverse
reactions include mild to moderate diarrhea, an asymptomatic in-
crease of blood uric acid and transaminases, and a decrease in the
neutrophil counts.13 Favipiravir dosage regimen for the treatment
of EBOV infection in the JIKI trial and the targeted concentra-
tions were estimated based on in vitro experiment (99% inhibitory
concentration 29  µg/mL), preclinical data in the mouse model
(150  mg/kg every 12  hours led to an average concentration of
59 µg/mL), 54% plasma protein binding in humans, and a pharma-
cokinetic model assessed with PK parameters estimated in healthy
volunteers.14 A 6,000  mg (2,400  mg, 2,400  mg, and 1,200  mg
q8h) loading dose on day 1 followed by a 2,400 mg maintenance
dose (1,200 mg q12h) on day 2 to day 9 was well tolerated.18 The
mean steady-state trough concentration was 46.1 µg/mL on day
2 (48 hours after the initial dose) and fell to 25.9 µg/mL on day
4 (96 hours after the initial dose).18 Both of these concentrations
were significantly lower than the predicted targeted concentra-
tions of 54.3 and 64.4 µg/mL, respectively.18 Regardless, the trial
provided a reference to evaluate the efficacy of favipiravir in pa-
tients with COVID-19 in a circumstance without the preliminary
in vitro and preclinical data. The up-to-date clinical study from
China showed that the regiment of 3,200  mg (1,600  mg twice
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daily) loading dose on day 1 followed by 1,200 mg maintenance
dose (600 mg twice daily) on day 2 to day 14 is effective.11 Of note,
previous clinical trials suggest that the plasma concentration of fa-
vipiravir in patients in the United States is 50% of that in Japanese
patients,13 suggesting a possible ethnic or regional difference in its
pharmacokinetics, which should not be ignored. As data concern-
ing the concentrations of the activated metabolite T-705RTP in
the tissues and the inactivated metabolite T705M1 in plasma for
these populations are not available, it is difficult to infer whether
the difference in plasma concentration of favipiravir was resulted
from differential tissue distribution or metabolic inactivation in
the liver, or even differential absorption after oral administration.
REGARDING POTENTIAL DRUG–DRUG INTERACTION IN
PHARMACOKINETICS
Multiple drug use is inevitable in the treatment of COVID-19,
especially for patients with basic diseases (hypertension, dia-
betes, and cardiovascular diseases) and complications (such as
acute respiratory distress syndrome, shock, arrhythmia, and
acute kidney injury) commonly observed in the patients with
COVID-19. 20,21 DDI is a topic that requires attention in clinical
practice. Information about DDI caused by favipiravir is limited
at present. Favipiravir is metabolized in the liver by AO in the
cytosol, but not by enzymes in the microsomes. Published data
are not available as to whether favipiravir and the active metab-
olite T-705-RTP affect activities of the hepatic drug-metabo-
lizing enzymes. A previous study in healthy volunteers showed
that concomitant administration of favipiravir increased the area
under the curve (AUC) of acetaminophen and acetaminophen
glucuronide by 20% and 23–34%, respectively, whereas the AUC
of acetaminophen sulfate decreased by 29–35%, and the excre-
tion of acetaminophen and the acetaminophen glucuronide in-
creased in urine. 22 Co-incubation of favipiravir with human liver
S9 inhibits acetaminophen sulfate formation with an IC50 value
of 24 µg/mL, suggesting inhibition on the sulfate transferase. 22
When combined with favipiravir, the recommended maximum
daily doses of acetaminophen are 3 g.
In vitro study demonstrates that selective estrogen receptor modu-
lators (raloxifene, tamoxifen, and estradiol), the H2 receptor antag-
onist cimetidine, calcium channel blockers (felodipine, amlodipine,
and verapamil), the anti-arrhythmic drug propafenone, and the
tricyclic antidepressant amitriptyline are potent AO inhibitors
(Table 2).23 Although the clinically relevant DDI based on AO inhi-
bition has yet to be established, an obvious DDI between cimetidine
and zaleplon is reported.24 Cimetidine coadministration results in
a marked inhibition on AO catalyzed oxozaleplon formation and a
warning is included in the zaleplon label.25 Potential DDIs between
these drugs and favipiravir should be carefully monitored. Several
drugs, such as citalopram,26 zaleplon,27 famciclovir,28 and sulindac,29
are also metabolized by AO. In vitro study shows that favipiravir is
a mechanism based inhibitor of AO in a concentration-dependent
manner between 3.14 and 942  µg/mL15 and the previous clinical
study showed a mean steady-state trough concentration of 46.1 µg/
mL in the treatment of EVD.18 Therefore, potential DDIs between
favipiravir and these latter drugs should also be monitored with
caution.
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Table 2  Inhibition of drugs and xenobiotics on human AO at 50 µM and the IC50 values
Percentage of control activity IC50 (μM)
Drug Indication or use (mean ± SD) (mean ± SE)
Raloxifene Antiosteoporotic <1.0 0.0029 ± 0.0003
Perphenazine Antipsychotic 1.2 ± 0.2 0.033 ± 0.011
Thioridazine Antipsychotic 7.1 ± 3.9 0.16 ± 0.07
Menadione Prothrombogenic 4.1 ± 0.5 0.20 ± 0.04
Trifluoperazine Antipsychotic 8.0 ± 1.9 0.24 ± 0.08
Amitriptyline Antidepressant 9.4 ± 4.7 0.26 ± 0.07
Estradiol Estrogen 7.4 ± 3.3 0.29 ± 0.07
Felodipine Antihypertensive/anti-anginal 7.0 ± 5.4 0.30 ± 0.08
Clomipramine Antidepressant 18 ± 6 0.48 ± 0.17
Loratadine Antihistaminic 7.3 ± 1.4 0.49 ± 0.13
Promethazine Antipsychotic 10 ± 3 0.51 ± 0.26
Chlorpromazine Antipsychotic 3.1 ± 2.5 0.57 ± 0.15
Ethinyl estradiol Oral contraceptive 6.2 ± 8.1 0.57 ± 0.15
Norclomipramine Antidepressant 11 ± 2 0.60 ± 0.14
Amodiaquine Antimalarial 11 ± 3 0.74 ± 0.07
Nortriptyline Antidepressant 7.5 ± 0.7 0.85 ± 0.46
Maprotiline Antidepressant 6.6 ± 2.0 1.4 ± 0.3
Quetiapine Antipsychotic 6.0 ± 0.0 1.4 ± 0.6
Promazine Antipsychotic 13 ± 0 1.6 ± 0.5
Loperamide Antidiarrheal 20 ± 4 10 ± 6
Erythromycin Antibacterial 16 ± 2 15 ± 6
Ondansetron Anti-emetic 5.9 ± 3.1 2.1 ± 0.8
Tamoxifen Anti-estrogen 8.9 ± 4.5 2.2 ± 1.5
Loxapine Anxiolytic 12 ± 5 2.3 ± 0.8
Propafenone Anti-arrhythmic 20 ± 9 2.5 ± 1.0
Domperidone Anti-emetic 10 ± 5 3.0 ± 1.4
Cyclobenzaprine Muscle relaxant 19 ± 4 3.1 ± 1.2
Quinacrine Anthelmintic/antimalarial 16 ± 6 3.3 ± 0.3
Verapamil Anti-anginal/anti-arrhythmic 16 ± 4 3.5 ± 1.5
Ketoconazole Antifungal 19 ± 8 3.5 ± 1.6
Metoclopramide Anti-emetic 14 ± 10 31 ± 1
Clozapine Antipsychotic 18 ± 2 4.4 ± 1.8
Tacrine Cognitive enhancer 8.0 ± 4.5 5.0 ± 3.8
Amlodipine Antihypertensive/anti-anginal 12 ± 6 5.5 ± 1.9
Olanzapine Antipsychotic 13 ± 7 6.0 ± 2.0
Salmeterol Bronchodilator 11 ± 2 9.9 ± 6.8
AO, aldehyde oxidase; IC50, half-maximal inhibitory concentration.

CONCLUSION Potential DDIs due to AO inhibition should not be ignored in

Favipiravir provides a substitute for compassionate use in
COVID-19 based on its mechanism of action inhibiting virus
RdRp and safety data in previous clinical studies. Data obtained
from influenza treatment and proof-of-concept clinical trial in
EVD aids the determination of dose regimen in clinical trials
or experimental use of the drug in COVID-19. However, the
exact efficacy of favipiravir awaits further clinical confirmation.
the clinical setting.
SEARCH STRATEGY AND SELECTION CRITERIA
References have been searched using the PubMed database with
the key words “Favipiravir” or “T705” and “Pharmacokinetics”
or “Clinical trials.” Information about the clinical trials for
COVID-19 was searched in the ClinicalTrials.gov website

246 VOLUME 108 NUMBER 2 | Month 2020 | www.cpt-journal.com


(http://www.chictr.org.cn/searc​
hproj.aspx) using key words
“COVID-19,” “2019-nCoV,” or “2019 novel coronavirus,” or
“Favipiravir,” or “T705.”
FUNDING
This work was supported by the National Key R&D Program  of China
(No. 2017YFC0909302) and the National Natural Science Foundation
of China (No. 81673518).
CONFLICT OF INTEREST
Both authors declared no competing interests for this work.
© 2020 The Authors Clinical Pharmacology & Therapeutics © 2020 American
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